Substituted 1-indolylpropyl-4-benzylpiperazine derivatives

ABSTRACT

A class of 1- 3-(1H-indol-3-yl)propyl!-4-benzylpiperazine derivatives of formula I, substituted at the 5-position of the indole nucleus by a 1,2,4-triazol-4-yl moiety, and on the methylene linkage of the benzyl moiety by a range of substituted alkyl groups, are selective agonists of 5-HT 1  -like receptors, being potent agonists of the human 5-HT 1D α  receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT 1D α  receptor subtype relative to the 5-HT 1D β  subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT 1D  receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT 1D  receptor agonists. ##STR1##

The present invention relates to a class of substituted piperazinederivatives which act on 5-hydroxytryptamine (5-HT) receptors, beingselective agonists of so-called "5-HT₁ -like" receptors. They aretherefore useful in the treatment of clinical conditions for which aselective agonist of these receptors is indicated.

It has been known for some time that 5-HT₁ -like receptor agonists whichexhibit selective vasoconstrictor activity are of use in the treatmentof migraine (see, for example, A. Doenicke et al., The Lancet, 1988,Vol. 1, 1309-11; and W. Feniuk and P. P. A. Humphrey, Drug DevelopmentResearch, 1992, 26, 235-240).

The human 5-HT₁ -like or 5-HT_(1D) receptor has recently been shown bymolecular cloning techniques to exist in two distinct subtypes. Thesesubtypes have been termed 5-HT_(1D)α (or 5-HT_(1D-1)) and 5-HT_(1D)β (or5-HT_(1D-2)), and their amino acid sequences are disclosed and claimedin WO-A-91/17174.

The 5-HT_(1D)α receptor subtype in humans is believed to reside onsensory terminals in the dura mater. Stimulation of the 5-HT_(1D)αsubtype inhibits the release of inflammatory neuropeptides which arethought to contribute to the headache pain of migraine. The human5-HT_(1D)β receptor subtype, meanwhile, is located predominantly on theblood vessels and in the brain, and hence may play a part in mediatingconstriction of cerebral and coronary arteries, as well as CNS effects.

Administration of the prototypical 5-HT_(1D) agonist sumatriptan(GR43175) to humans is known to give rise at therapeutic doses tocertain adverse cardiovascular events (see, for example, F. Willett etal., Br. Med. J., 1992, 304, 1415; J. P. Ottervanger et al., The Lancet,1993, 341, 861-2; and D. N. Bateman, The Lancet, 1993, 341, 221-4).Since sumatriptan barely discriminates between the human 5-HT_(1D)α and5-HT_(1D)β receptor subtypes (cf. WO-A-91/17174, Table 1), and since itis the blood vessels with which the 5-HT_(1D)β subtype is most closelyassociated, it is believed that the cardiovascular side-effects observedwith sumatriptan can be attributed to stimulation of the 5-HT_(1D)βreceptor subtype. It is accordingly considered (cf G. W. Rebeck et al.,Proc. Natl. Acad. Sci. USA, 1994, 91, 3666-9) that compounds which caninteract selectively with the 5-HT_(1D)α receptor subtype, whilst havinga less pronounced action at the 5-HT_(1D)β subtype, might be free from,or at any rate less prone to, the undesirable cardiovascular and otherside-effects associated with non-subtype-selective 5-HT_(1D) receptoragonists, whilst at the same time maintaining a beneficial level ofanti-migraine activity.

The compounds of the present invention, being selective 5-HT₁ -likereceptor agonists, are accordingly of benefit in the treatment ofmigraine and associated conditions, e.g. cluster headache, chronicparoxysmal hemicrania, headache associated with vascular disorders,tension headache and paediatric migraine. In particular, the compoundsaccording to this invention are potent agonists of the human 5-HT_(1D)αreceptor subtype. Moreover, the compounds in accordance with thisinvention have been found to possess at least a 10-fold selectiveaffinity for the 5-HT_(1D)α receptor subtype relative to the 5-HT_(1D)βsubtype, and they can therefore be expected to manifest fewerside-effects than those associated with non-subtype-selective 5-HT_(1D)receptor agonists.

Several distinct classes of substituted five-membered heteroaromaticcompounds are described in published European patent application0497512, and published International patent applications 93/18029,94/02477 and 94/03446. The compounds described therein are stated to beagonists of 5-HT₁ -like receptors, and accordingly to be of particularuse in the treatment of migraine and associated conditions. None ofthese publications, however, discloses nor even suggests the substitutedpiperazine derivatives provided by the present invention.

In EP-A-0548813 is described a series of alkoxypyridin-4-yl andalkoxypyrimidin-4-yl derivatives of indol-3-ylalkylpiperazines which arealleged to provide treatment of vascular or vascular-related headaches,including migraine. There is, however, no disclosure nor any suggestionin EP-A-0548813 of replacing the alkoxypyridine or alkoxypyrimidinesubstituent with a substituted benzyl moiety; nor is there anysuggestion therein that the range of substituents specified at the5-position of the indole moiety might be replaced by a1,2,4-triazol-4-yl ring.

Moreover, nowhere in the prior art mentioned above is there anydisclosure of a subtype-selective 5-HT_(1D) receptor agonist having a5-HT_(1D)α receptor binding affinity (IC₅₀) below 50 nM and at least a10-fold selective affinity for the 5-HT_(1D)α receptor subtype relativeto the 5-HT_(1D)β subtype.

The compounds according to the present invention are subtype-selective5-HT_(1D) receptor agonists having a human 5-HT_(1D)α receptor bindingaffinity (IC₅₀) below 50 nM, typically below 10 nM and preferably below1 nM; and at least a 10-fold selective affinity, typically at least a50-fold selective affinity and preferably at least a 100-fold selectiveaffinity, for the human 5-HT_(1D)α receptor subtype relative to the5-HT_(1D)β subtype. Moreover, the compounds in accordance with thisinvention possess interesting properties in terms of their efficacyand/or bioavailability.

The present invention provides a compound of formula I, or a salt orprodrug thereof: ##STR2## wherein R¹ represents hydrogen, halogen,trifluoromethyl, C₁₋₆ alkoxy or a group of formula (a): ##STR3## R² andR³ independently represent hydrogen, halogen, trifluoromethyl or C₁₋₆alkoxy;

E represents a straight or branched alkylene chain containing from 1 to4 carbon atoms; and

Z represents hydroxy, C₁₋₆ alkoxy, aryl(C₁₋₆)alkoxy, an imidazolyl orpyrrolidinyl group, or a group of formula (Za) or (Zb): ##STR4## inwhich the broken line represents an optional chemical bond; and R⁴represents C₁₋₆ alkyl.

The compounds in accordance with the present invention are encompassedwithin the generic scope of co-pending International Patent ApplicationNo. PCT/GB95/01129, published as WO 95/32196 on Nov. 30, 1995. There is,however, no specific disclosure therein of compounds corresponding tothose of formula I above wherein R¹, R², R³, E and Z are as definedabove.

As used herein, the expression "C₁₋₆ alkyl" includes methyl and ethylgroups, and straight-chained or branched propyl, butyl, pentyl and hexylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyland tert-butyl. Derived expressions such as "C₁₋₆ alkoxy" are to beconstrued accordingly.

The term "aryl" as used herein includes phenyl and naphthyl.

A typical aryl(C₁₋₆)alkoxy group is benzyloxy.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine, especially fluorine.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention have at least one asymmetriccentre, and they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

In the compounds of formula I above, the moiety R¹ suitably representshydrogen, fluoro, trifluoromethyl, methoxy or a group of formula (a) asdefined above. Particular values of R¹ include hydrogen, fluoro andtrifluoromethyl, especially hydrogen or fluoro.

Suitably, R² and R³ independently represent hydrogen, fluoro,trifluoromethyl or methoxy, in particular hydrogen or fluoro. Suitably,one or both of R² and R³ represents hydrogen.

Suitably, R⁴ represents methyl.

The alkylene chain E in the compounds of formula I above may be, forexample, methylene, ethylene, 1-methylethylene, propylene,2-methylpropylene or butylene. Suitably, E represents a methylene orethylene linkage.

Particular values for the substituent Z include hydroxy, methoxy,benzyloxy, imidazol-1-yl, pyrrolidin-1-yl, oxazol-2-on-3-yl,oxazolidin-2-on-3-yl and 5-methyl-1,2,4-oxadiazol-3-yl.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula II, and salts and prodrugsthereof: ##STR5## wherein R¹, R² and R³ are as defined above; e is 1 or2; and

Z¹ represents hydroxy, methoxy, benzyloxy, imidazol-1-yl,pyrrolidin-1-yl, oxazol-2-on-3-yl, oxazolidin-2-on-3-yl or5-methyl-1,2,4-oxadiazol-3-yl.

Particular values of R¹ in relation to formula II above includehydrogen, fluoro and trifluoromethyl, especially hydrogen or fluoro.

In one embodiment of the compounds of formula II above, R² is hydrogenand R³ is other than hydrogen.

In another embodiment of the compounds of formula II above, R² and R³are both hydrogen.

Specific compounds within the scope of the present invention include:

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(oxazol-2-on-3-yl)-1-phenylethyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(oxazolidin-2-on-3-yl)-1-phenylethyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-(oxazolidin-2-on-3-yl)ethyl!piperazine;

1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(3-hydroxy-1-phenylpropyl)piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(imidazol-1-yl)-1-phenylethyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-hydroxyethyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-methoxyethyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1-phenylpropyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-benzyloxy-1-(4-fluorophenyl)ethyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-3-methoxypropyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-(imidazol-1-yl)ethyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-phenyl-2-(pyrrolidin-1-yl)ethyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-3-hydroxypropyl!piperazine;

1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-(imidazol-1-yl)-1-phenylpropyl!piperazine;

and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of migraine, a suitable dosage level is about 0.01 to250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The compounds according to the invention may be prepared by a processwhich comprises reacting the compound of formula III with a compound offormula IV: ##STR6## wherein R¹, R², R³, E and Z are as defined above,and L¹ represents a suitable leaving group.

The leaving group L¹ is suitably a halogen atom, e.g. chlorine orbromine, or an alkylsulphonyloxy or arylsulphonyloxy group, e.g.methanesulphonyloxy (mesyloxy) or p-toluenesulphonyloxy (tosyloxy).

The reaction between compounds III and IV is conveniently effected bystirring the reactants under basic conditions in a suitable solvent, forexample triethylamine or potassium carbonate in N,N-dimethylformamide orisopropanol, typically in the presence of sodium iodide.

In another procedure, the compounds according to the invention may beprepared by a process which comprises reacting the compound of formulaIII as defined above with a compound of formula V: ##STR7## wherein R¹,R², R³, E and Z are as defined above; in the presence of a reducingagent.

A suitable reducing agent for effecting this process is sodiumcyanoborohydride, and the reaction is conveniently carried out inmethanol, typically in the presence of acetic acid, at room temperature.

The compound of formula III above may be prepared by a process whichcomprises reacting the compound of formula VI: ##STR8## with a compoundof formula VII, or a carbonyl-protected form thereof: ##STR9## whereinR^(p) represents an amino-protecting group; with subsequent removal ofthe amino-protecting group R^(p).

The reaction between compounds VI and VII, which is an example of thewell-known Fischer indole synthesis, is suitably carried out by heatingthe reagents together under mildly acidic conditions, e.g. 4% sulphuricacid at reflux.

Suitable carbonyl-protected forms of the compounds of formula VIIinclude the dimethyl acetal derivatives.

The protecting group R^(p) in the compounds of formula VII is suitably acarbamoyl moiety such as tert-butoxycarbonyl (BOC), which canconveniently be removed as necessary by treatment under mildly acidicconditions. Indeed, the acidic conditions of the Fischer indolesynthesis reaction will generally suffice to remove the BOC group.

The Fischer reaction between compounds VI and VII may be carried out ina single step, or may proceed via an initial non-cyclising step at alower temperature to give an intermediate of formula VIII: ##STR10##wherein R^(p) is as defined above; followed by cyclisation using asuitable reagent, e.g. a polyphosphate ester.

The intermediates of formula VII, or carbonyl-protected forms thereof,may be prepared by reacting a compound of formula IX, or acarbonyl-protected form thereof, with a compound of formula X: ##STR11##wherein R^(p) is as defined above, and L² represents a suitable leavinggroup.

The leaving group L² is suitably a halogen atom, e.g. chlorine orbromine.

Where L² represents a halogen atom, the reaction between compounds IXand X is conveniently effected by stirring the reactants under basicconditions in a suitable solvent, for example potassium carbonate inN,N-dimethylformamide, or triethylamine in tetrahydrofuran oracetonitrile.

The compounds according to the invention may alternatively be preparedby a process which comprises reacting the compound of formula VI asdefined above with a compound of formula XI, or a carbonyl-protectedform thereof: ##STR12## wherein R¹, R², R³, E and Z are as definedabove; under conditions analogous to those described above for thereaction between compounds VI and VII.

As for the compounds of formula VII, suitable carbonyl-protected formsof the compounds of formula XI include the dimethyl acetal derivatives.

As with that between compounds VI and VII, the Fischer reaction betweencompounds VI and XI may be carried out in a single step, or may proceedvia an initial non-cyclising step at a lower temperature to give anintermediate of formula XII: ##STR13## wherein R¹, R², R³, E and Z areas defined above; followed by cyclisation using a suitable reagent, e.g.a polyphosphate ester.

The intermediates of formula XI, or carbonyl-protected forms thereof,may be prepared by reacting a compound of formula IX as defined above,or a carbonyl-protected form thereof, with a compound of formula XIII:##STR14## wherein R¹, R², R³, E and Z are as defined above; underconditions analogous to those described above for the reaction betweencompounds IX and X.

In an alternative procedure, the compounds of formula III above may beprepared by a process which comprises reacting a compound of formula Xas defined above with a compound of formula XIV: ##STR15## wherein L³represents a suitable leaving group; followed by removal of theamino-protecting group R^(p).

Similarly, the compounds of formula I as defined above may be preparedby a process which comprises reacting a compound of formula XIII asdefined above with a compound of formula XIV as defined above.

The leaving group L³ is suitably an alkylsulphonyloxy orarylsulphonyloxy group, e.g. methanesulphonyloxy (mesyloxy) orp-toluenesulphonyloxy (tosyloxy).

Where L³ represents an alkylsulphonyloxy or arylsulphonyloxy group, thereaction between compound XIV and compound X or XIII is convenientlycarried out in a suitable solvent such as 1,2-dimethoxyethane orisopropyl alcohol, typically in the presence of a base such as sodiumcarbonate or potassium carbonate, optionally with the addition of sodiumiodide.

In one representative approach, the compounds of formula XIV wherein L³represents a mesyloxy or tosyloxy group may be prepared by the sequenceof steps illustrated in the following reaction scheme (cf. Larock andYum, J. Am. Chem. Soc., 1991, 113, 6689): ##STR16## wherein L⁴represents mesyloxy or tosyloxy, and TMS is an abbreviation fortrimethylsilyl.

In Step 1 of the reaction scheme, the aniline derivative XV is treatedwith iodine monochloride, advantageously in methanol in the presence ofa base such as calcium carbonate, in order to introduce an iodine atomortho to the amine moiety. Step 2 involves a palladium-mediated couplingreaction with the protected acetylene derivative TMS--C.tbd.C--(CH₂)₃--OH, typically using palladium acetate and triphenylphosphine in thepresence of lithium chloride and sodium carbonate, suitably inN,N-dimethylformamide at an elevated temperature. This is followed inStep 3 by removal of the TMS moiety, ideally in refluxing methanolichydrochloric acid; followed in turn by mesylation or tosylation,suitably by using mesyl chloride or tosyl chloride respectively inpyridine.

In another representative approach, the compounds of formula XIV whereinL³ represents a mesyloxy or tosyloxy group may be prepared by reacting3,4-dihydro-2H-pyran with the compound of formula VI as defined above ora salt thereof, under a variant of the Fischer reaction conditions asdescribed above for the reaction between compounds VI and VII; followedby mesylation or tosylation of the 3-hydroxypropyl-indole derivativethereby obtained, typically by treatment with mesyl chloride or tosylchloride under standard conditions.

The Fischer reaction with 3,4-dihydro-2H-pyran is suitably brought aboutby heating the hydrazine derivative VI or an acid addition salt thereof,typically the hydrochloride salt, in an inert solvent such as dioxan,advantageously in the presence of a mineral acid such as hydrochloricacid or a Lewis acid such as zinc chloride, at the reflux temperature ofthe solvent.

In a further procedure, the compounds of formula III above may beprepared by a process which comprises reducing a compound of formulaXVI: ##STR17## wherein R^(p) is as defined above; with subsequentremoval of the amino-protecting group R^(p).

Similarly, the compounds according to the invention may be prepared by aprocess which comprises reducing a compound of formula XVII: ##STR18##wherein R¹, R², R³, E and Z are as defined above.

The reduction of compound XVI or compound XVII is conveniently effectedby treating the appropriate compound with a reducing agent such aslithium aluminium hydride in an appropriate solvent, e.g. diethyl etheror tetrahydrofuran, or mixtures thereof.

The compounds of formulae XVI and XVII above may suitably be prepared byreacting the appropriate compound of formula X or XIII with a compoundof formula XVIII: ##STR19## wherein J represents a reactive carboxylatemoiety.

Suitable values for the reactive carboxylate moiety J include esters,for example C₁₋₄ alkyl esters; acid anhydrides, for example mixedanhydrides with C₁₋₄ alkanoic acids; acid halides, for example acidchlorides; and acylimidazoles.

By way of example, the intermediates of formula XVIII above wherein J isan acid chloride moiety may be prepared by treating the correspondingcarboxylic acid derivative with thionyl chloride in toluene. Similarly,the intermediates of formula XVIII wherein J is an acylimidazole moietymay be prepared by treating the corresponding carboxylic acid derivativewith 1,1'-carbonyldiimidazole. Alternatively, the reactive carboxylatemoiety J may be obtained by treating the corresponding compound whereinJ is carboxy with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and 1-hydroxybenzotriazole hydrate, optionally in thepresence of triethylamine; the resulting activated carboxylateintermediate may then suitably be reacted in situ with the requiredcompound of formula X or XIII.

In a still further procedure, the compounds of formula I above wherein Zrepresents hydroxy may be prepared by a process which comprises reducinga compound of formula XIX: ##STR20## wherein E¹ represents a chemicalbond or a straight or branched alkylene chain containing from 1 to 3carbon atoms, R^(x) represents C₁₋₆ alkyl, and R¹, R² and R³ are asdefined above.

The reduction of the ester functionality in compound XIX mayconveniently be effected by treatment with a reducing agent such aslithium aluminium hydride, typically in a solvent such astetrahydrofuran.

In a yet further procedure, the compounds of formula I above wherein Zrepresents imidazol-1-yl, pyrrolidin-1-yl, oxazol-2-on-3-yl oroxazolidin-2-on-3-yl may be prepared by a process which comprisesreacting a compound of formula XX with a compound of formula XXI:##STR21## wherein Z² represents imidazol-1-yl, pyrrolidin-1-yl,oxazol-2-on-3-yl or oxazolidin-2-on-3-yl, L⁵ represents a suitableleaving group, and R¹, R², R³ and E are as defined above.

The leaving group L⁵ suitably represents mesyloxy or tosyloxy.

Where Z² represents an oxazol-2-on-3-yl moiety, compound XXI isdesirably treated with a strong base such as sodium hydride, in order togenerate the anion thereof prior to reaction with compound XX. In thiscontext, a suitable solvent is N,N-dimethylformamide, and the reactionis typically carried out at room temperature. Otherwise, the reactionbetween compounds XX and XXI can be effected in the absence of addedbase, and will conveniently be accomplished in tetrahydrofuran assolvent, at an elevated temperature under sealed tube conditions.

Where the leaving group L⁵ is mesyloxy or tosyloxy, the intermediate offormula XX may conveniently be prepared by mesylation or tosylationrespectively of the corresponding compound of formula I wherein Z ishydroxy. The latter compound may conveniently be prepared by reductionof the appropriate compound of formula XIX as described above.

The hydrazine derivative of formula VI above can be prepared by themethod described in WO 94/03446, as also can the aniline derivative offormula XV.

Where they are not commercially available, the starting materials offormula IV, V, IX, X, XIII, XVIII, XIX and XXI may be prepared bymethods analogous to those described in the accompanying Examples, or bystandard procedures well known from the art.

It will be appreciated that any compound of formula I initially obtainedfrom any one of the above processes may, where appropriate, subsequentlybe elaborated into a further compound of formula I using techniquesknown from the art. For example, a compound of formula I wherein Z ishydroxy initially obtained may be converted into the correspondingcompound wherein Z is amino by mesylation of the hydroxy group withmesyl chloride under standard conditions, followed by treatment withammonia in methanol/tetrahydrofuran in a sealed tube at an elevatedtemperature; the resulting amino compound can then be treated with2-chloroethyl chloroformate to yield the respective chloroethylcarbamate derivative, with subsequent ring closure by treatment withsodium hydride to afford the desired compound of formula I wherein Zrepresents an oxazolidin-2-on-3-yl moiety.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The novel compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The novel compounds may, for example, beresolved into their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with the present invention potently andselectively bind to the 5-HT_(1D)α receptor subtype, inhibitforskolin-stimulated adenylyl cyclase activity, and stimulate ³⁵S!-GTPγS binding to membranes from clonal cell lines expressing humancloned receptors.

5-HT_(1D)α /5-HT_(1D)β Radioligand Binding

Chinese hamster ovary (CHO) clonal cell lines expressing the human5-HT_(1D)α and 5-HT_(1D)β receptors were harvested in PBS andhomogenised in ice cold 50 mM Tris-HCl (pH 7.7 at room temperature) witha Kinematica polytron and centrifuged at 48,000 g at 4° C. for 11 min.The pellet was then resuspended in 50 mM Tris-HCl followed by a 10 minincubation at 37° C. Finally the tissue was recentrifuged at 48,000 g,4° C. for 11 min and the pellet resuspended, in assay buffer(composition in mM: Tris-HCl 50, pargyline 0.01, CaCl₂ 4; ascorbate0.1%; pH 7.7 at room temperature) to give the required volumeimmediately prior to use (0.2 mg protein/ml). Incubations were carriedout for 30 min at 37° C. in the presence of 0.02-150 nM ³ H!-5-HT forsaturation studies or 2-5 nM ³ H!-5-HT for displacement studies. Thefinal assay volume was 1 ml. 5-HT (10 μM) was used to definenon-specific binding. The reaction was initiated by the addition ofmembrane and was terminated by rapid filtration through Whatman GF/Bfilters (presoaked in 0.3% PEI/0.5% Triton X) followed by 2×4 mlwashings with 50 mM Tris-HCl. The radioactive filters were then countedon a LKB beta or a Wallac beta plate counter. Binding parameters weredetermined by non-linear, least squares regression analysis using aniterative curve fitting routine, from which IC₅₀ (the molarconcentration of compound necessary to inhibit binding by 50%) valuescould be calculated for each test compound. The IC₅₀ values for bindingto the 5-HT_(1D)α receptor subtype obtained for the compounds of theaccompanying Examples were below 50 nM in each case. Furthermore, thecompounds of the accompanying Examples were all found to possess aselective affinity for the 5-HT_(1D)α receptor subtype of at least10-fold relative to the 5-HT_(1D)β subtype.

5-HT_(1D)α /5-HT_(1D)β Adenylyl Cyclase Assay

Studies were performed essentially as described in J. Pharmacol. Exp.Ther., 1986, 238, 248. CHO clonal cell lines expressing the human cloned5-HT_(1D)α and 5-HT_(1D)β receptors were harvested in PBS andhomogenised, using a motor driven teflon/glass homogeniser, in ice coldTris HCl-EGTA buffer (composition in mM: Tris HCl 10, EGTA 1, pH 8.0 atroom temperature) and incubated on ice for 30-60 min. The tissue wasthen centrifuged at 20,000 g for 20 min at 4° C., the supernatantdiscarded and the pellet resuspended in Tris HCl-EDTA buffer(composition in mM: Tris HCl 50, EDTA 5, pH 7.6 at room temperature)just prior to assay. The adenylyl cyclase activity was determined bymeasuring the conversion of α- ³³ P!-ATP to ³³ P!-cyclic AMP. A 10 μlaliquot of the membrane suspension was incubated, for 10-15 min, in afinal volume of 50 μl, at 30° C., with or without forskolin (10 μM), inthe presence or absence of test compound. The incubation bufferconsisted of 50 mM Tris HCl (pH 7.6 at room temperature), 100 mM NaCl,30 μM GTP, 50 μM cyclic AMP, 1 mM dithiothreitol, 1 mM ATP, 5 mM MgCl₂,1 mM EGTA, 1 mM 3-isobutyl-1-methylxanthine, 3.5 mM creatininephosphate, 0.2 mg/ml creatine phosphokinase, 0.5-1 μCi α- ³³ P!-ATP and1 nCi ³ H!-cyclic AMP. The incubation was initiated by the addition ofmembrane, following a 5 min preincubation at 30° C., and was terminatedby the addition of 100 μl SDS (composition in mM: sodium lauryl sulphate2%, ATP 45, cyclic AMP 1.3, pH 7.5 at room temperature). The ATP andcyclic AMP were separated on a double column chromatography system(Anal. Biochem., 1974, 58, 541). Functional parameters were determinedusing a least squares curve fitting programme ALLFIT (Am. J. Physiol.,1978, 235, E97) from which E_(max) (maximal effect) and EC₅₀ (the molarconcentration of compound necessary to inhibit the maximal effect by50%) values were obtained for each test compound. Of those compoundswhich were tested in this assay, the EC₅₀ values for the 5-HT_(1D)αreceptor obtained for the compounds of the accompanying Examples werebelow 500 nM in each case. Moreover, the compounds of the accompanyingExamples which were tested were all found to possess at least a 10-foldselectivity for the 5-HT_(1D)α receptor subtype relative to the5-HT_(1D)β subtype.

5-HT_(1D)α /5-HT_(1D)β GTPγS Binding

Studies were performed essentially as described in Br. J. Pharmacol.,1993, 109, 1120. CHO clonal cell lines expressing the human cloned5-HT_(1D)α and 5-HT_(1D)β receptors were harvested in PBS andhomogenised using a Kinematica polytron in ice cold 20 mM HEPEScontaining 10 mM EDTA, pH 7.4 at room temperature. The membranes werethen centrifuged at 40,000 g, 4° C. for 15 min. The pellet was thenresuspended in ice cold 20 mM HEPES containing 0.1 mM EDTA, pH 7.4 atroom temperature and recentrifuged at 40,000 g, 4° C. for 15-25 minutes.The membranes were then resuspended in assay buffer (composition in mM:HEPES 20, NaCl 100, MgCl₂ 10, pargyline 0.01; ascorbate 0.1%; pH 7.4 atroom temperature) at a concentration of 40 μg protein/ml for the5-HT_(1D)α receptor transfected cells and 40-50 μg protein/ml for the5-HT_(1D)β receptor transfected cells. The membrane suspension was thenincubated, in a volume of 1 ml, with GDP (100 μM for 5-HT_(1D)α receptortransfected cells, 30 μM for the 5-HT_(1D)β receptor transfected cells)and test compound at 30° C. for 20 min and then transferred to ice for afurther 15 min. ³⁵ S!-GTPγS was then added at a final concentration of100 pM and the samples incubated for 30 min at 30° C. The reaction wasinitiated by the addition of membrane and was terminated by rapidfiltration through Whatman GF/B filters and washed with 5 ml water. Theradioactive filters were then counted on a LKB beta counter. Functionalparameters were determined by a non-linear, least squares regressionanalysis using an iterative curve fitting routine, from which E_(max)(maximal effect) and EC₅₀ (the molar concentration of compound necessaryto inhibit the maximal effect by 50%) values were obtained for each testcompound. Of those compounds which were tested in this assay, the EC₅₀values for the 5-HT_(1D)α receptor obtained for the compounds of theaccompanying Examples were below 500 nM in each case. Moreover, thecompounds of the accompanying Examples which were tested were all foundto possess at least a 10-fold selectivity for the 5-HT_(1D)α receptorsubtype relative to the 5-HT_(1D)β subtype.

EXAMPLE 1 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-hydroxy-1-phenylpropyl!piperazine. 1.9 Hydrogen Oxalate

Intermediate 1

4-(1,2,4-Triazol-4-yl)phenylhydrazine

Prepared as described in WO 94/03446, Example 1.

Intermediate 2

1-(3- 5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl!propyl)-4-(H)-piperazine. 3.5Hydrogen Oxalate

1. 5- 4-(tert-Butyloxycarbonyl)piperazin-1-yl!pentanal dimethyl acetal

a) 5-Bromopentanal dimethyl acetal

To a solution of 5-bromovaleryl chloride (50 g, 0.251 mol) in anhydrousTHF (500 ml), at -78° C., was added lithiumtri-tert-butoxyaluminohydride (1.0M solution in tetrahydrofuran, 300 ml;0.30 mol), keeping the temperature below -70° C. The solution wasstirred at -78° C. for 5 h and then quenched by dropwise addition of 2Mhydrochloric acid (350 ml). The mixture was warmed to room temperatureand stirred for 16 h. Diethyl ether (500 ml) was added, the aqueousphase separated and extracted further with ether (×2). The combinedextracts were washed with saturated Na₂ CO₃ solution (×1), water (×1)and brine (×2), dried (Na₂ SO₄) and evaporated to give5-bromovaleraldehyde (37.5 g, 91%). A solution of 5-bromovaleraldehyde(37.5 g, 0.227 mol) in methanol (250 ml) and concentrated sulphuric acid(0.5 ml) was stirred at room temperature for 3 h. The solvent wasremoved under vacuum and to the residue was added K₂ CO₃ solution (50ml) and diethyl ether (500 ml). The aqueous layer was separated andre-extracted with ether (×2). The combined extracts were washed withwater and brine, dried (Na₂ SO₄) and evaporated. The crude product waschromatographed on silica gel eluting with diethyl ether/hexane (1:9) togive the title-acetal (27.5 g, 57%). δ(250 MHz, CDCl₃) 1.43-1.67 (4H, m,2 of CH₂); 1.83-1.94 (2H, m, CH₂); 3.38 (6H, s, CH(OMe)₂); 3.42 (2H, t,J=7 Hz, CH₂ Br), 4.37 (1H, t, J=7 Hz, CH(OMe)₂).

b) 5- 4-(tert-Butyloxycarbonyl)piperazin-1-yl!pentanal dimethyl acetal

A mixture of 5-bromovaleraldehyde dimethyl acetal (27.5 g, 0.13 mol),Na₂ CO₃ (20.7 g, 0.195 mol), sodium iodide (19.5 g, 0.13 mol) andtert-butyl-1-piperazinecarboxylate (25.5 g, 0.137 mol), indimethoxyethane (250 ml), was heated at 100° C. for 3 h. Aluminium foilwas wrapped around the vessel to exclude light. The mixture was cooledto room temperature and filtered. The filtrate was evaporated underreduced pressure and then EtOAc (50 ml) added and the mixture filteredagain to remove inorganic salts. The solvent was removed under vacuumand the residue chromatographed on silica gel eluting with EtOAc to givethe title-product (25.7 g, 63%). δ(250 MHz, CDCl₃) 1.29-1.71 (6H, m, 3of CH₂); 1.46 (9H, s, OC(Me)₃); 2.31-2.39 (6H, m, 3 of CH₂); 3.32 (6H,s, CH(OMe)₂); 3.41-3.45 (4H, m, 2 of CH₂); 4.36 (1H, t, J=6 Hz,CH(OMe)₂).

2. 1-(3- 5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl!propyl)-4-(H)-piperazine.3.5 Hydrogen Oxalate

A mixture of Intermediate 1 (5.0 g, 28.6 mmol) and 5-4-(tert-butyloxycarbonyl)piperazin-1-yl!pentanal dimethylacetal (9.03 g,28.6 mmol) in 4% sulphuric acid (150 ml) was heated at reflux for 48 h.The solution was cooled in an ice-bath, basified with solid K₂ CO₃ andextracted with butan-1-ol (×3). The solvent was removed under vacuum andazeotroped with hexane (×2). The crude product was purified bychromatography on silica gel eluting with CH₂ Cl₂ /MeOH/NH₃ (30:8:1) togive the title-indole (3.9 g, 44%). The 3.5 hydrogen oxalate salt wasprepared using 200 mg of free base: mp 90-92° C. (Found: C, 45.97; H,4.76; N, 13.77. C₁₇ H₂₂ N₆.3.5(C₂ H₂ O₄) requires C, 46.08; H, 4.76; N,13.43%); δ(360 MHz, D₂ O) 2.12-2.24 (2H, m, CH₂); 2.93 (2H, t, J=7 Hz,CH₂); 3.46-3.76 (8H, m, 4 of CH₂); 7.37 (1H, dd, J=1.9 and 8.7 Hz,Ar--H); 7.39 (1H, s, Ar--H); 7.66 (1H, d, J=8.7, Ar--H); 7.82 (1H, d,J=1.9 Hz, Ar--H); 9.13 (2H, s, Triazole-H).

Step 1

3-Bromo-3-phenylpropan-1-ol

To a solution of 3-phenylpropan-1-ol (5 mL, 0.037 mol) in CCl₄ (60 mL)was added N-bromosuccinimide (6.5 g, 0.037 mol) and benzoyl peroxide(383 mg of 70% technical grade, 1.1 mmol). The mixture was heated atreflux for 3 h, after which time the solution was cooled and filtered.The filtrate was removed in vacuo and the residue partitioned betweenEt₂ O (100 mL) and water (100 mL). The organic layer was separated,dried (Na₂ SO₄) and evaporated. The residue was chromatographed onsilica gel, eluting with petrol:EtOAc (2:1), to give the bromide (3.7 g,47%) as a colourless oil. ¹ H NMR (250 MHz, CDCl₃) δ2.13-2.26 (1H, m),2.36-2.49 (1H, m), 3.40-3.53 (2H, m), 5.36 (1H, dd, J=8.9 and 5.9 Hz),7.27-7.49 (5H, m).

Step 2

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-hydroxy-1-phenylpropyl!piperazine. 1.9 Hydrogen Oxalate

A solution of Intermediate 2 (250 mg, 0.81 mmol),3-bromo-3-phenylpropan-1-ol (191 mg, 0.89 mmol) and K₂ CO₃ (111 mg, 0.81mmol) in DMF (7 mL) was heated at 70° C. for 2 h. After this time morebromide (38 mg, 0.17 mmol) was added and heating continued for a further2 h. The solvent was then removed in vacuo and the residue partitionedbetween CH₂ Cl₂ (2×20 mL) and water (20 mL). The combined organic layerswere dried (Na₂ SO₄) and evaporated. The residue was chromatographed onsilica gel, eluting with CH₂ Cl₂ :MeOH:NH₃ (95:5:1), to afford the titlepiperazine (228 mg, 64%) as a colourless oil. The hydrogen oxalate saltwas prepared. mp. 153° C. C₂₆ H₃₂ N₆ O. 1.9 (C₂ H₂ O₄) requires: C,58.14; H, 5.86; N, 13.65%. Found: C, 57.79; H, 5.85; N, 13.92%. ¹ H NMR(360 MHz, d₆ -DMSO) δ1.79-1.87 (1H, m), 1.88-2.01 (2H, m), 2.04-2.15(1H, m), 2.59-2.80 (4H, m), 2.82-3.39 (10H, m), 3.70-3.77 (1H, m),7.24-7.36 (7H, m), 7.49 (1H, d, J=8.5 Hz), 7.77 (1H, s), 8.99 (2H, s),11.16 (1H, br s). MS (ES⁺) (445, M+1).

EXAMPLE 2 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-3-hydroxypropyl!piperazine. 1.5 Hydrogen Oxalate

Step 1

Ethyl 3-(4-fluorophenyl)prop-2-enoate

A solution of 4-fluorobenzaldehyde (8.6 mL, 0.081 mol) andcarboethoxymethylene triphenylphosphorane (34 g, 0.097 mol) in toluene(400 mL) was heated at reflux for 3 h. After this time the solvent wasremoved in vacuo and the residue triturated in petrol:Et₂ O (1:1). Themixture was filtered and the filtrate evaporated. The residue waschromatographed on silica gel, eluting with petrol:Et₂ O (3:1), toafford the ester (14.4 g, 92%) as a low-melting colourless solid. ¹ HNMR (major isomer) (250 MHz, CDCl₃) δ1.34 (3H, t, J=7.0 Hz), 4.26 (2H,q, J=7.0 Hz), 6.36 (1H, d, J=16 Hz), 7.07 (2H, dd, J_(HA-HB) =8.6 Hz andJ_(HA-F) =8.6 Hz), 7.51 (2H, dd, J_(HB-HA) =8.6 Hz and J_(HB-F) =5.3Hz), 7.65 (1H, d, J=16 Hz).

Step 2

3-Bromo-3-(4-fluorophenyl)propan-1-ol

A solution of the alkene (14.4 g, 0.074 mol) in EtOH (200 mL) containing10% Pd on C (1.0 g) was hydrogenated at 40 psi for 40 min. After thistime the catalyst was removed by filtration and the filtrate evaporated.The residue was azeotroped with EtOH (50 mL) and the crude ester (14 g)isolated as a colourless oil and used directly without furtherpurification.

To a stirred solution of the saturated ester (14 g) in THF (300 mL) at-10° C., under nitrogen, was added LiAlH₄ (78 mL of a 1.0M solution inEt₂ O, 78 mmol) dropwise. After addition was complete the solution wasstirred for a further 1 h at 0° C. A solution of Na₂ SO₄ (sat., 50 mL)was added and the solid removed by filtration. The filtrate was removedin vacuo and the residue partitioned between Et₂ O (200 mL) and water(200 mL). The organic layer was separated, dried (Na₂ SO₄) andevaporated. The crude 3-(4-fluorophenyl)propan-1-ol (11 g) was isolatedas a colourless oil and used directly without further purification. To asolution of the alcohol (5 g, prepared from above) in CCl₄ (100 mL) wasadded N-bromosuccinimide (5.8 g, 0.032 mol) and benzoyl peroxide (331 mgof 70% technical grade, 0.96 mmol). The mixture was heated at reflux for3 h then the solution was cooled to room temperature and filtered. Thefiltrate was evaporated and the residue chromatographed on silica gel,eluting with petrol:Et₂ O (2:1→1:1). The bromide (3.52 g, 47%) wasisolated as a pale yellow oil. ¹ H NMR (250 MHz, CDCl₃) δ2.23-2.36 (1H,m), 2.41-2.55 (1H, m), 3.67-3.90 (2H, m), 5.22 (1H, dd, J=9.3 and 5-7Hz), 7.04 (2H, dd, J_(HA-HB) =8.6 Hz and J_(HA-F) =8.6 Hz), 7.39 (2H,dd, J_(HB-HA) =8.6 Hz and J_(HB-F) =5.3 Hz).

Step 3

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-3-hydroxypropyl!piperazine. 1.5 Hydrogen Oxalate

Prepared as described in Example 1, Step 2 using Intermediate 2 (381 mg,1.22 mmol), 3-bromo-3-(4-fluorophenyl)propan-1-ol (369 mg, 1.59 mmol),K₂ CO₃ (168 mg, 1.22 mmol) and DMF (9 mL). The crude residue waschromatographed on silica gel, eluting with CH₂ Cl₂ :MeOH (95:5→90:10),to afford the title piperazine (411 mg, 73%) as a pale yellow oil. Thehydrogen oxalate salt was prepared. mp. 134° C. C₂₆ H₃₁ N₆ OF. 1.5 (C₂H₂ O₄). H₂ O requires: C, 56.58; H, 5.89; N, 13.65%. Found C, 56.28; H,6.05; N, 13.44%. ¹ H NMR (250 MHz, d₆ -DMSO) δ1.70-2.13 (4H, m),2.64-3.39 (14H, m), 3.72-3.76 (1H, m), 7.15 (2H, dd, J_(HA-HB) =8.9 Hzand J_(HA-F) =8.9 Hz), 7.22-7.30 (4H, m), 7.45 (1H, d, J=8.6 Hz), 7.73(1H, d, J=2.0 Hz), 8.97 (2H, s), 11.15 (1H, br s). MS (ES⁺) (463, M+1).

EXAMPLE 3 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-3-methoxypropyl!-piperazine. 1.5 Hydrogen Oxalate

Step 1

3-Bromo-3-(4-fluorophenyl)-1-methoxypropane

To a stirred solution of 3-(4-fluorophenyl)propan-1-ol (800 mg, 5.2mmol) (see Example 2, Step 2) in DMF (20 mL), under nitrogen, was addedsodium hydride (250 mg of a 60% dispersion in mineral oil, 6.24 mmol).The mixture was stirred at 0° C. for 20 min then iodomethane (389 μL,6.24 mmol) was added. Stirring was continued for 30 min then the coolingbath was removed and the mixture stirred at room temperature for 1 h.After this time more sodium hydride (125 mg of a 60% dispersion inmineral oil, 3.1 mmol) followed by iodomethane (195 μL, 3.1 mmol) wereadded and the mixture stirred for a further 2 h. The solvent was removedin vacuo and the residue partitioned between ether (2×50 mL) and water(50 mL). The combined organic layers were dried (Na₂ SO₄) andevaporated. The crude methyl ether (593 mg), which was isolated as acolourless oil, was used in the subsequent reaction without furtherpurification.

To a solution of the ether (590 mg) (prepared as described above) inCCl₄ (20 mL) was added N-bromosuccinimide (625 mg, 3.51 mmol) andbenzoyl peroxide (36 mg of 70% technical grade, 0.1 mmol). The mixturewas heated at reflux for 1 h then the solution was cooled to roomtemperature and filtered. The filtrate was removed in vacuo and theresidue chromatographed on silica gel, eluting with petrol:Et₂ O (8:1).The bromide (304 mg, 35%) was isolated as a colourless oil. ¹ H NMR (250MHz, CDCl₃) δ2.22-2.36 (1H, m), 2.40-2.55 (1H, m), 3.33 (3H, s),3.36-3.43 (1H, m), 3.49-3.58 (1H, m), 5.17 (1H, dd, J=6.0 and 9.0 Hz),7.02 (2H, dd, J_(HA-HB) =8.6 Hz and J_(HA-F) =8.6 Hz), 7.38 (2H, dd,J_(HB-HA) =8.6 Hz and J_(HB-F) =5.2 Hz).

Step 2

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-3-methoxyproyl!piperazine. 1.5 Hydrogen Oxalate

Prepared as described in Example 1, Step 2 using Intermediate 2 (200 mg,0.65 mmol), 3-bromo-3-(4-fluorophenyl)-1-methoxypropane (237 mg, 0.96mmol), K₂ CO₃ (89 mg, 0.65 mmol) and DMF (10 mL). The crude residue waschromatographed on silica gel, eluting with CH₂ Cl₂ :MeOH:NH₃(90:10:0→90:10:1), to afford the title piperazine (163 mg, 53%) as thefree base. The hydrogen oxalate salt was prepared. mp. 166° C. C₂₇ H₃₃N₆ FO. 1.5(C₂ H₂ O₄). 1.2(H₂ O) requires: C, 56.90; H, 6.11; N, 13.27%.Found: C,57.23; H, 6.46; N, 13.07%. ¹ H NMR (360 MHz, d₆-DMSO)δ1.83-2.05 (3H, m), 2.13-2.22 (1H, m), 2.67-3.35 (17H, m),3.70-3.74 (1H, m), 7.18 (2H, dd, J_(HA-HB) =8.8 Hz and J_(HA-F) =8.8Hz), 7.28-7.32 (4H, m), 7.49 (1H, d, J=8.5 Hz), 7.77 (1H, d, J=1.9 Hz),8.99 (2H, s), 11.15 (1H, br s). MS (ES⁺) (477, M+1).

EXAMPLE 4 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1-phenylpropyl!piperazine. 1.5Hydrogen Oxalate

Intermediate 3

3- 5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl!propan-1-ol

A solution of Intermediate 1 (25 g, 143 mmol) in dioxan (250 mL) wastreated with dihydropyran (24 g, 286 mmol) followed by 1M hydrochloricacid (150 mL) and heated at reflux for 18 h. The mixture was evaporatedthen azeotroped with toluene. Inorganic solids were removed by treatingthe residue with a mixture of methanol and acetonitrile. The motherliquors were chromatographed on silica gel, eluting with CH₂ Cl₂ :MeOH(9:1→4:1). The compound was recrystallised from acetonitrile to affordthe title alcohol (10.24 g, 30%) as a colourless solid. mp. 205-207° C.¹ H NMR (360 MHz, d₆ -DMSO) δ1.81 (2H, quin, J=7.0 Hz), 2.75 (2H, t,J=8.0 Hz), 3.46 (2H, dt, J=6.0 and 5.0 Hz), 4.43 (1H, t, J=5.0 Hz), 7.26(1H, d, J=2.0 Hz), 7.29 (1H, dd, J=9.0 and 2.0 Hz), 7.47 (1H, d, J=9.0Hz), 7.77 (1H, d, J=2.0 Hz), 9.01 (2H, s), 11.05 (1H, br s). MS (CI⁺)(243, M+1).

Step 1

4-Bromo-4-phenylbutyronitrile

Prepared as described in Example 1, Step 1 using 4-phenylbutyronitrile(5.2 mL, 0.034 mol), N-bromosuccinimide (6.65 g, 0.037 mol), benzoylperoxide (352 mg of 70% technical grade. 1.0 mmol) and CCl₄ (60 mL). Thecrude residue was chromatographed on silica gel, eluting with petrol:Et₂O (3:1). The bromide (5.62 g, 74%) was isolated as a colourless oil. ¹ HNMR (250 MHz, CDCl₃) δ2.36-2.64 (4H, m), 5.00-5.07 (1H, m), 7.29-7.43(5H, m).

Step 2

4-(4-tert-Butyloxycarbonylpiperazinyl)-4-phenylbutyronitrile

A solution of 1-(tert-butyloxycarbonyl)piperazine (1.73 g, 9.3 mmol),4-bromo-4-phenylbutyronitrile (2.5 g, 11 mmol) and K₂ CO₃ (1.4 g, 10.2mmol) in DMF (40 mL) was heated at 60° C. for 4 h. After this time themixture was cooled to room temperature, filtered and the filtrateevaporated. The residue was partitioned between EtOAc (100 mL) and water(100 mL). The organic layer was separated, dried (Na₂ SO₄) andevaporated. The residue was chromatographed on silica gel, eluting withpetrol:EtOAc (2:1). The piperazine (2.69 g, 88%) was isolated as a paleyellow oil, which solidified on standing in the fridge. ¹ H NMR (250MHz, CDCl₃) δ1.41 (9H, s), 1.94-2.46 (8H, m), 3.32-3.60 (5H, m),7.15-7.42 (5H, m). MS (ES⁺) (330, M+1).

Step 3

4-(4-tert-Butyloxycarbonylpiperazinyl)-4-phenylbutyl carboxamide Oxime

To a solution of sodium methoxide in MeOH (183 mg sodium in 25 mL MeOH,8.0 mmol) was added hydroxylamine hydrochloride (0.55 g, 8.0 mmol). Themixture was stirred at room temperature for 15 min then4-(4-tert-butyloxycarbonylpiperazinyl)-4-phenylbutyronitrile (2.62 g,8.0 mmol) was added. The mixture was heated at reflux for 16 h then thesolution was cooled to room temperature. The mixture was filtered,evaporated and the residue partitioned between EtOAc (60 mL) and water(60 mL). The organic layer was separated, dried (Na₂ SO₄) and evaporatedin vacuo. The residue was chromatographed on silica gel, eluting withCH₂ Cl₂ :MeOH (90:10), to afford the amide oxime (934 mg, 32%). ¹ H NMR(360 MHz, d₆ -DMSO) δ1.34 (9H, s), 1.73-2.30 (8H, m), 3.19-3.30 (4H, m),3.39-3.45 (1H, m), 5.32 (2H, br s), 7.19-7.36 (5H, m), 8.70 (1H, s).

Step 4

3- 3-4-(tert-Butyloxycarbonyl)piperazin-1-yl!-3-phenyl!propyl-5-methyl-1,2,4-oxadiazole

To a solution of sodium methoxide in MeOH (59 mg sodium in 20 mL MeOH,2.56 mmol) at room temperature was added the amide oxime (0.93 g, 2.56mmol) followed by EtOAc (1.25 mL). The mixture was heated at reflux for2 days before more sodium (30 mg, 1.3 mmol) was added. Heating wascontinued for one further day before the addition of more sodium (30 mg,1.3 mmol) followed by EtOAc (1.25 mL). Heating at reflux was continuedfor 3 days before more sodium (30 mg, 1.3 mmol) and EtOAc (1.25 mL) wereadded. After heating for a further 2 days the solution was cooled toroom temperature and the solvent evaporated. The residue was partitionedbetween EtOAc (20 mL) and water (2×20 mL). The organic phase wasseparated, dried (Na₂ SO₄) and evaporated. The residue waschromatographed on silica gel, eluting with petrol:EtOAc (1:1→0:1). Theoxadiazole (783 mg, 79%) was isolated as a colourless oil. ¹ H NMR (360MHz, CDCl₃) δ1.41 (9H, s), 2.08-2.42 (6H, m), 2.53 (3H, s), 2.59-2.70(2H, m), 3.31-3.48 (5H, m), 7.20-7.38 (5H, m).

Step 5

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1-phenylpropyl!piperazine. 1.5Hydrogen Oxalate

A solution of the oxadiazole (390 mg, 1.0 mmol) in CH₂ Cl₂ (20 mL) andtrifluoroacetic acid (4 mL) was stirred at room temperature overnight.The solvent was removed in vacuo and the residue partitioned between CH₂Cl₂ (2×20 mL) and aqueous K₂ CO₃ (10%, 20 mL). The combined organiclayers were dried (Na₂ SO₄) and evaporated. The crude amine (276 mg) wasused without further purification.

To a solution of Intermediate 3 (150 mg, 0.62 mmol) in THF (80 mL),under nitrogen, at room temperature, was added triethylamine (188 μL,1.36 mmol) and methanesulphonyl chloride (105 μL, 1.36 mmol). Afterstirring for 1 h more triethylamine (60 μL, 0.43 mmol) followed bymethanesulphonyl chloride (30 μL, 0.39 mmol) were added. After stirringfor a further 30 min more triethylamine (30 μL, 0.21 mmol) andmethanesulphonyl chloride (15 μL, 0.20 mmol) were added. After a further30 min the solution was filtered and the filtrate evaporated in vacuo.The crude mesylate was used in the subsequent reaction without furtherpurification.

To a solution of the crude mesylate in iso-propanol (25 mL) was addedthe crude amine (276 mg, prepared as described above), sodium iodide (93mg, 0.62 mmol) and K₂ CO₃ (297 mg, 1.43 mmol). The mixture was heated atreflux for 4 h. The solution was then cooled and filtered and thefiltrate evaporated. The residue was partitioned between CH₂ Cl₂ (2×20mL) and water (20 mL) and the combined organic layers dried (Na₂ SO₄)and evaporated. The residue was chromatographed on silica gel, elutingwith CH₂ Cl₂ :MeOH:NH₃ (95:5:0→90:10:0→90:10:1). The title piperazine(196 mg, 62%) was isolated as a cream-coloured foam. The hydrogenoxalate salt was prepared. mp. 134° C. C₂₉ H₃₄ N₈ O. 1.5(C₂ H₂ O₄).0.5(H₂ O) requires: C, 58.71; H, 5.85; N, 17.12%. Found: C, 58.65; H,6.20; N, 16.82%. ¹ H NMR (360 MHz, d₆ -DMSO) δ1.90-2.10 (3H, m),2.26-2.40 (1H, m), 2.42-3.30 (17H, m), 3.57-3.63 (1H, m), 7.25-7.40 (7H,m), 7.49 (1H, d, J=8.6 Hz), 7.77 (1H, s), 8.99 (2H, s), 11.16 (1H, brs). MS (ES⁺) (511, M+1).

EXAMPLE 5 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-hydroxyethyl!piperazine. 1.1 Hydrogen Oxalate

Step 1

Methyl 2-bromo-2-(4-fluorophenyl)ethyl acetate

To a stirred solution of thionyl chloride (4.8 mL, 0.066 mol) in MeOH(100 mL) at 0° C., under nitrogen, was added 4-fluorophenylacetic acid(5.1 g, 0.033 mol) portionwise. The cooling bath was removed and thesolution stirred at room temperature for 2 h. The solvents were removedin vacuo and the crude methyl ester was isolated as a colourless oil.The ester was used in the subsequent reaction without furtherpurification.

A solution of this ester, N-bromosuccinimide (6.17 g, 0.035 mol) andbenzoyl peroxide (342 mg of 70% technical grade, 0.99 mol) in CCl₄ (60mL) was heated at reflux, under nitrogen, for 1 h. After this time thesolvent was evaporated and the residue partitioned between ether (100mL) and water (100 mL). The organic layer was separated, dried (Na₂ SO₄)and evaporated. The residue was chromatographed on silica gel, elutingwith petrol:Et₂ O (3:1), to afford the title bromide (7.33 g, 90%) as apale yellow oil. ¹ H NMR (250 MHz, CDCl₃) δ3.80 (3H, s), 5.34 (1H, s),7.05 (2H, dd, J_(HA-HB) =8.7 Hz and J_(HA-F) =8.7 Hz), 7.53 (2H, dd,J_(HB-HA) =8.7 Hz and J_(HB-F) =5.2 Hz).

Step 2

Methyl 2-(4-fluorophenyl)-2-1-(3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl)piperazin-4-yl!ethylacetate

In the same was as that described in Example 1, Step 2, usingIntermediate 2 (620 mg, 2.0 mmol), methyl2-bromo-2-(4-fluorophenyl)ethyl acetate (543 mg, 2.2 mmol), K₂ CO₃ (304mg, 2.2 mmol) and DMF (15 mL). The crude residue was chromatographed onsilica gel, eluting with CH₂ Cl₂ :MeOH (90:10) to afford the ester (0.85g, 82%) as a yellow foam. ¹ H NMR (250 MHz, CDCl₃) δ1.87-2.03 (2H, m),2.37-2.71 (10H, m), 2.79 (2H, t, J=7.4 Hz), 3.68 (3H, s), 3.97 (1H, s),7.03 (2H, dd, J_(HA-HB) =8.6 Hz and J_(HA-F) =8.6 Hz), 7.12-7.16 (2H,m), 7.38-7.49 (3H, m), 7.55 (1H, dd, J=1.7 Hz), 8.44 (1H, br s), 8.46(2H, s). MS (ES⁺) (477, M+1).

Step 3

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-hydroxyethyl!piperazine. 1.1 Hydrogen Oxalate

To a solution of the methyl ester (785 mg, 1.65 mmol) in THF (30 mL) at-10° C., was added LiAlH₄ (1.65 mL of a 1.0M solution in ether, 1.65mmol) dropwise. The mixture was stirred at -10° C. for 30 min beforemore LiAlH₄ (0.33 mL of a 1.0M solution in ether, 0.33 mmol) was added.After a further 30 min Na₂ SO₄ solution (sat., 2 mL) was added dropwiseand the cooling bath removed. The mixture was stirred for 30 min thenthe undissolved solid was removed by filtration. The filtrate wasevaporated and the residue chromatographed on silica gel, eluting withCH₂ Cl₂ :MeOH:NH₃ (90:10:0→90:10:1). The alcohol (671 mg, 91%) wasisolated as a pale yellow foam. The hydrogen oxalate salt was prepared.mp. 110° C. (dec.). C₂₅ H₂₉ N₆ OF. 1.1(C₂ H₂ O₄). H₂ O requires: C,57.76; H, 5.92; N, 14.86%. Found: C, 58.06; H, 6.02; N, 14.54%. ¹ H NMR(360 MHz, d₆ -DMSO) δ1.91-2.03 (2H, m), 2.37-3.20 (12H, m), 3.50-3.57(1H, m), 3.63-3.70 (1H, m), 3.72-3.77 (1H, m), 7.16 (2H, dd, J_(HA-HB)=8.8 Hz and J_(HA-F) =8.8 Hz), 7.30-7.36 (4H, m), 7.49 (1H, d, J=8.5Hz), 7.77 (1H, s), 9.00 (2H, s), 11.16 (1H, br s). MS (ES⁺) (449, M+1).

EXAMPLE 6 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-(imidazol-1-yl)ethyl!piperazine. 2.6 HydrogenOxalate

To a solution of 1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-hydroxyethyl!piperazine (200 mg, 0.45 mmol) in THF(10 mL) at 0° C. was added triethylamine (124 μL, 0.89 mmol) followed bymethanesulphonyl chloride (70 μL, 0.89 mmol). The mixture was stirred at0° C. for 20 min then the mixture filtered and the filtrate transferredto a sealed tube. Imidazole (608 mg, 8.9 mmol) was added and the mixtureheated at 70° C. for 1 h. After this time the solvent was evaporated andthe residue partitioned between CH₂ Cl₂ (50 mL) and water (3×40 mL). Theorganic phase was separated, dried (Na₂ SO₄) and evaporated. The residuewas chromatographed on silica gel, eluting with CH₂ Cl₂ :MeOH:NH₃(90:10:1). The imidazole (72 mg, 32%) was isolated as a pale yellowfoam. The hydrogen oxalate salt was prepared. mp. 93° C. (dec.). C₂₈ H₃₁N₈ F. 2.6(C₂ H₂ O₄). 1.1(H₂ O) requires: C, 52.99; H, 5.14; N, 14.89%.Found: C, 52.76; H, 5.27; N, 15.07%. ¹ H NMR (360 MHz, d₆ -DMSO)δ1.97-2.10 (2H, m), 2.49-3.60 (14H, m), 5.70-5.75 (1H, m), 7.10 (1H, s),7.22 (2H, dd, J_(HA-HB) =8.8 Hz and J_(HA-F) =8.8 Hz), 7.30-7.36 (2H,m), 7.41-7.46 (3H, m), 7.50 (1H, d, J=8.6 Hz), 7.80 (1H, s), 8.21 (1H,s), 9.01 (2H, s), 11.18 (1H, br s), MS (ES⁺) (499, M+1).

EXAMPLE 7 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-(oxazolidin-2-on-3-yl)ethyl!piperazine. 2.0Hydrogen Oxalate

Step 1

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-amino-1-(4-fluorophenyl)ethyl!piperazine

In the same way as that described in Example 6 using 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-hydroxyethyl!piperazine (113 mg, 0.25 mmol),triethylamine (70 μL, 0.50 mmol), methanesulphonyl chloride (39 μL, 0.50mmol) and THF (5 mL). The crude mesylate was converted to the amine inthe same manner as that used in Example 6, using ammonia (2.5 mL of a 2Msolution in MeOH, 5.0 mmol). The amine (60 mg, 53%) was isolated as apale yellow foam. ¹ H NMR (250 MHz, CDCl₃) δ1.89-2.01 (2H, m), 2.27-2.85(14H, m), 4.10 (1H, dd, J=10.1 and 3.8 Hz), 7.00 (2H, dd, J_(HA-HB) =8.7Hz and J_(HA-F) =8.7 Hz), 7.13-7.16 (2H, m), 7.34 (2H, dd, J_(HB-HA)=8.7 Hz and J_(HB-F) =5.5 Hz), 7.47 (1H, d, J=8.6 Hz), 7.57 (1H, d,J=1.9 Hz), 8.37 (1H, br s), 8.47 (2H, s). MS (ES⁺) (448, M+1).

Step 2

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(2-chloroethylcarbamoyl)-1-(4-fluorophenyl)ethyl!-piperazine

To a solution of 1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-amino-1-(4-fluorophenyl)ethyl!piperazine (60 mg, 0.13 mmol) in dioxane(2 mL) and water (1 mL) was added NaOH (59 μL of a 10%(w/v) aqueoussolution, 0.15 mmol), followed by 2-chloroethyl chloroformate (15 μL,0.14 mmol). The mixture was stirred at room temperature for 45 min thenthe solution was adjusted to pH 11 using aqeuous NaOH. The mixture wasstirred for a further 30 min then the solvent removed in vacuo. Theresidue was partitioned between EtOAc (2×2 mL) and water (20 mL). Thecombined organic layers were dried (Na₂ SO₄) and evaporated. The residuewas chromatographed on silica gel, eluting with CH₂ Cl₂ :MeOH (90:10).The carbamate (47 mg, 63%) was isolated as a colourless foam. ¹ H NMR(250 MHz, CDCl₃) δ1.90-2.03 (2H, m), 2.37-2.92 (14H, m), 3.53-3.77 (2H,m), 4.20-4.31 (2H, m), 4.55-4.69 (1H, m), 5.77-5.88 (1H, m), 7.01 (2H,dd, J_(HA-HB) =8.7 Hz and J_(HA-F) =8.7 Hz), 7.13-7.28 (4H, m), 7.47(1H, d, J=8.6 Hz), 7.56 (1H, d, J=2.0 Hz), 8.39 (1H, br s), 8.47 (2H,s). MS (ES⁺) (554/556, M+1).

Step 3

1- 3-(5-(1 2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-(oxazolidin-2-on-3-yl)ethyl!piperazine 2.0 HydrogenOxalate

To a solution of the carbamate (47 mg, 0.085 mmol) in DMF (5 mL) wasadded sodium hydride (3.4 mg of a 60% dispersion in mineral oil, 0.085mmol), and the mixture stirred at room temperature for 45 min. Themixture was then partitioned between CH₂ Cl₂ (2×20 mL) and water (20mL). The combined organic layers were dried (Na₂ SO₄) and evaporated.The residue was chromatographed on silica gel, eluting with CH₂ Cl₂:MeOH:NH₃ (90:10:0→90:10:1). The oxazolidinone (15 mg, 34%) was isolatedas a colourless gum. The hydrogen oxalate salt was prepared. mp. 128° C.(dec.). C₂₈ H₃₂ N₇ O₂ F. 2.0(C₂ H₂ O₄). 0.7(H₂ O) requires: C, 54.11; H,5.31; N, 13.80%. Found: C, 54.12; H, 5.14; N, 13.73%. ¹ H NMR (360 MHz,d₆ -DMSO) δ1.98-2.10 (2H, m), 2.67-3.20 (12H, m), 3.21-3.30 (1H, m),3.51-3.63 (1H, m), 4.19-4.30 (4H, m), 4.98-5.03 (1H, m), 7.20 (2H, dd,J_(HA-HB) =8.9 Hz and J_(HA-F) =8.9 Hz), 7.31-7.34 (2H, m), 7.40 (2H,dd, J_(HB-HA) =8.7 Hz and J_(HB-F) =5.5 Hz), 7.49 (1H, d, J=8.7 Hz),7.79 (1H, s), 9.01 (2H s), 11.17 (1H, br s). MS (ES⁺) (518, M+1).

EXAMPLE 8 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl-2-methoxyethyl!piperazine 1.4 Hydrogen Oxalate

Step 1

Methyl 2-(4-tert-butyloxycarbonylpiperazin-1-yl)-2-(4-fluorophenyl)ethylacetate

To a solution of methyl 2-bromo-2-(4-fluorophenyl)ethyl acetate (3.6 g,14.6 mmol) in DMF (30 mL) was added 1-(tert-butyloxycarbonyl)piperazine(2.71 g, 14.6 mmol) and K₂ CO₃ (2.41 g, 17.5 mmol). The mixture washeated at 50° C. for 45 min then the solvent was evaporated. The residuewas partitioned between EtOAc (150 mL) and water (100 mL). The organiclayer was separated, dried (Na₂ SO₄) and evaporated. The residue waschromatographed on silica gel, eluting with hexane:EtOAc (4:1→2:1), toafford the title piperazine (4.65 g, 91%) as a yellow oil. ¹ H NMR (360MHz, d₆ -DMSO) δ1.37 (9H, s), 2.30-2.36 (4H, m), 3.26-3.31 (4H, m), 3.62(3H, s), 4.22 (1H, s), 7.20 (2H, dd, J_(HA-HB) =8.9 Hz and J_(HA-F) =8.9Hz), 7.42 (2H, dd, J_(HB-HA) =8.9 Hz and J_(HB-F) =5.6 Hz). MS (ES⁺)(353, M+1).

Step 2

2- 4-tert-Butyloxycarbonylpiperazin-1-yl!2- 4-fluorophenyl!ethan-1-ol

To a solution of the ester (4.65 g, 13.2 mmol) in THF (100 mL) at -10°C. was added LiAlH₄ (13.2 mL of a 1.0M solution in ether, 13.2 mmol)dropwise. After stirring at -10° C. for 1 h Na₂ SO₄ solution (sat., 13.2mL) was added dropwise and the cooling bath removed. The mixture wasstirred for 30 min and the solid removed by filtration. The filtrate wasevaporated and the residue chromatographed on silica gel, eluting withEtOAc:petrol (1:1)→EtOAc:MeOH (99:1). The alcohol (4.17 g, 97%) wasisolated as a colourless oil. ¹ H NMR (360 MHz, d₆ -DMSO) δ1.36 (9H, s),2.24-2.41 (4H, m), 3.20-3.30 (4H, m), 3.42-3.46 (1H, m), 3.61-3.70 (1H,m), 3.74-3.83 (1H, m), 4.52 (1H, t, J=5.3 Hz), 7.13 (2H, dd, J_(HA-HB)=8.7 Hz and J_(HA-F) =8.7 Hz), 7.31 (2H, dd, J_(HB-HA) =8.7 Hz andJ_(HB-F) =5.7 Hz). MS (ES⁺) (325, M+1).

Step 3

4-(tert-Butyloxycarbonyl)-1-1-(4-fluorophenyl)-2-methoxyethyl!piperazine

To a solution of the alcohol in DMF (20 mL) at 0° C., was added sodiumhydride (204 mg of a 60% dispersion in oil, 5.1 mmol). After stirring at0° C. for 20 min iodomethane (0.32 mL, 5.1 mmol) was added and themixture stirred at 0° C. for a further 30 min. More sodium hydride (74mg of a 60% dispersion in oil, 1.9 mmol) followed by iodomethane (0.12mL, 1.9 mmol) were then added and the mixture stirred for 20 min at 0°C. followed by 30 min at room temperature. The solvent was evaporatedand the residue partitioned between EtOAc (2×50 mL) and water (50 mL).The combined organic layers were dried (Na₂ SO₄) and evaporated. Theresidue was chromatographed on silica gel, eluting with EtOAc:hexane(1:1) to afford the methyl ether (1.46 g, 93%) as a colourless oil. ¹ HNMR (360 MHz, d₆ -DMSO) δ1.36 (9H, s), 2.26-2.37 (4H, m), 3.19 (3H, s),3.24-3.33 (4H, m), 3.59-3.71 (3H, m), 7.13 (2H, dd, J_(HA-HB) =8.9 Hzand J_(HA-F) =8.9 Hz), 7.33 (2H, dd, J_(HB-HA) =8.9 Hz and J_(HB-F) =5.7Hz). MS (ES⁺) (339, M+1).

Step 4

1- 1-(4-Fluorophenyl)-2-methoxyethyl!piperazine

To a solution of 4-(tert-butyloxycarbonyl)-1-1-(4-fluorophenyl)-2-methoxyethyl!piperazine (1.46 g, 4.3 mmol) in CH₂Cl₂ (40 mL) was added trifluoroacetic acid (4 mL), and the mixturestirred at room temperature for 3 h. The solvent was evaporated and theresidue azeotroped with toluene (2×20 mL). The residue was partitionedbetween EtOAc (2×50 mL) and Na₂ CO₃ solution (sat., 50 mL). The combinedorganic phases were dried (Na₂ SO₄) and evaporated. The residue waschromatographed on silica gel, eluting with CH₂ Cl₂ :MeOH:NH₃ (90:10:1),to afford the piperazine (0.95 g, 92%) as a pale yellow oil. ¹ H NMR(360 MHz, CDCl₃) δ2.37-2.55 (4H, m), 2.86-2.89 (4H, m), 3.29 (3H, s),3.45-3.48 (1H, m), 3.61 (1H, dd, J=9.9 and 5.2 Hz), 3.71 (1H, dd, J=9.9and 5.8 Hz), 7.00 (2H, dd, J_(HA-HB) =8.7 Hz and J_(HA-F) =8.7 Hz), 7.27(2H, dd, J_(HB-HA) =8.7 Hz and J_(HB-F) =5.6 Hz). MS (ES⁺) (239, M+1).

Step 5

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-methoxyethyl!piperazine. 1.4 Hydrogen Oxalate

To a solution of Intermediate 3 (125 mg, 0.52 mmol) in THF (80 mL) wasadded triethylamine (144 μL, 1.03 mmol) and methanesulphonyl chloride(80 μL, 1.03 mmol). After stirring at room temperature for 2 h moretriethylamine (72 μL, 0.51 mmol) followed by methanesulphonyl chloride(40 μL, 0.51 mmol) were added and the mixture stirred for a further 1 h.After this time the mixture was filtered and the filtrate evaporated invacuo. The crude mesylate was used in the subsequent reaction withoutfurther purification.

To a suspension of the crude mesylate (prepared above) in iso-propanol(20 mL) was added K₂ CO₃ (214 mg, 1.55 mmol), sodium iodide (77 mg, 0.52mmol) and a solution of 1- 1-(4-fluorophenyl)-2-methoxyethyl!piperazine(615 mg, 2.6 mmol) in iso-propanol (5 mL). The mixture was heated atreflux, in the dark, for 3 h. The solution was allowed to cool to roomtemperature and the precipitate removed by filtration. The filtrate wasevaporated and the residue partitioned between CH₂ Cl₂ (2×50 mL) andwater (50 mL). The combined organic layers were dried (Na₂ SO₄) andevaporated. The residue was chromatographed on silica gel, eluting withCH₂ Cl₂ :MeOH (9:1→4:1), to give the title indole (232 mg, 97%) as apale yellow foam. The hydrogen oxalate salt was prepared. mp. 100° C.(dec.). C₂₆ H₃₁ N₆ OF. 1.4(C₂ H₂ O₄). 1.5(H₂ O) requires: C, 56.19; H,6.03; N, 13.65%. Found: C, 56.56; H, 6.35; N, 13.34%. ¹ H NMR (360 MHz,d₆ -DMSO) δ1.91-2.03 (2H, m), 2.50-3.23 (15H, m), 3.58-3.62 (1H, m),3.67-3.71 (2H, m), 7.16 (2H, dd, J_(HA-HB) =8.9 Hz and J_(HA-F) =8.9Hz), 7.30-7.37 (4H, m), 7.49 (2H, d, J=8.5 Hz), 7.78 (1H, d, J=1.9 Hz),9.00 (2H, s), 11.17 (1H, br s). MS (ES⁺) (463, M+1).

EXAMPLE 9 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-benzyloxy-1-(4-fluorophenyl)ethyl!piperazine. 1.5 Hydrogen Oxalate

Step 1

1-2-Benzyloxy-1-(4-fluorophenyl)ethyl!-4-(tert-butyloxycarbonyl)piperazine

In the same way as that described in Example 8, Step 3 using 2-4-tert-butyloxycarbonylpiperazin-1-yl!-2- 4-fluorophenyl!ethan-1-ol (1.5g, 4.6 mmol), sodium hydride (204 mg of a 60% dispersion in oil, 5.1mmol) and benzyl bromide (0.61 mL, 5.1 mmol). After stirring at roomtemperature for 30 min more sodium hydride (37 mg of a 60% dispersion inoil, 0.92 mmol) followed by benzyl bromide (0.11 mL, 0.92 mmol) wasadded. The residue was chromatographed on silica gel, eluting withEtOAc:hexane (1:4→1:2), to afford the benzyl ether (1.58 g, 82%) as acolourless oil. ¹ H NMR (250 MHz, CDCl₃) δ1.43 (9H, s), 2.30-2.55 (4H,m), 3.33-3.45 (4H, m), 3.51-3.60 (1H, m), 3.61-3.71 (1H, m), 3.73-3.85(1H, m), 4.48 (2H, s), 6.96-7.04 (2H, m), 7.20-7.40 (7H, m). MS (ES⁺)(415, M+1).

Step 2

1- 2-Benzyloxy-1-(4-fluorophenyl)ethyl!piperazine

In the same way as that described in Example 8, Step 4 using 1-2-benzyloxy-1-(4-fluorophenyl)ethyl!-4-(tert-butyloxycarbonyl)piperazine(1.58 g, 3.8 mmol), trifluoroacetic acid (5 mL) and CH₂ Cl₂ (50 mL). Thepiperazine (1.11 g, 92%) was isolated as a colourless oil. ¹ H NMR (250MHz, CDCl₃) δ2.36-2.57 (4H, m), 2.84-2.89 (4H, m), 3.49-3.54 (1H, m),3.65 (1H, dd, J=9.9 and 5.4 Hz), 3.79 (1H, dd, J=9.9 and 5.8 Hz), 4.47(2H, s), 6.99 (1H, dd, J_(HA-HB) =8.7 Hz and J_(HA-F) =8.7 Hz),7.20-7.35 (7H, m). MS (ES⁺) (315, M+1).

Step 3

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-benzyloxy-1-(4-fluorophenyl)ethyl!piperazine. 1.5 Hydrogen Oxalate

In the same way as that described in Example 8, Step 5, usingIntermediate 3 (100 mg, 0.41 mmol), triethylamine (172 μL, 1.24 mmol),methanesulphonyl chloride (96 μL, 1.24 mmol) and THF (70 mL). Afterstirring at room temperature for 3 h more triethylamine (57 μL, 0.41mmol) followed by methanesulphonyl chloride (32 μL, 0.41 mmol) wereadded. After stirring at room temperature for a further 90 min theresultant crude mesylate was obtained and used crude in the subsequentreaction.

The crude mesylate (prepared above), 1-2-benzyloxy-1-(4-fluorophenyl)ethyl!piperazine (649 mg, 2.07 mmol), K₂CO₃ (171 mg, 1.24 mmol), sodium iodide (62 mg) and iso-propanol (20 mL)were converted to the title compound in the same way as that describedin Example 8, Step 5. The crude residue was chromatographed on silicagel, eluting with CH₂ Cl₂ :MeOH (92.5:7.5→85:15), to afford thepiperazine (136 mg, 61%) as a pale yellow foam. The hydrogen oxalatesalt was prepared. mp. 65° C. (dec.). C₃₂ H₃₅ N₆ OF. 1.5(C₂ H₂ O₄).0.3(H₂ O) requires: C, 61.90; H, 5.73; N, 12.38%. Found: C, 61.90; H,5.89; N, 12.46%. ¹ H NMR (360 MHz, d₆ -DMSO+TFA) δ2.00-2.08 (2H, m),2.50-3.76 (12H, m), 3.89-3.97 (1H, m), 4.02-4.11 (1H, m), 4.57-4.65 (3H,m), 7.27-7.46 (9H, m), 7.51-7.61 (3H, m), 7.95 (1H, s), 9.81 (2H, s),11.33 (1H, br s). MS (ES⁺) (539, M+1).

EXAMPLE 10 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(imidazol-1-yl)-1-phenylethyl!piperazine. 2.5 Hydrogen Oxalate

Intermediate 4

1-(3- 5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl!propyl)-4-2-hydroxy-1-phenylethyl!piperazine

a) Methyl 2-phenyl-2-1-(3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl)piperazin-4-yl!ethylacetate

In the same way as that described in Example 1, Step 2, usingIntermediate 2 (200 mg, 0.64 mmol), methyl α-bromophenyl acetate (112μL, 0.71 mmol), K₂ CO₃ (98 mg, 0.71 mmol) and DMF (5 mL). The cruderesidue was chromatographed on silica gel, eluting with CH₂ Cl₂ :MeOH(93:7), to afford the ester (205 mg, 70%) as a cream foam. ¹ H NMR (250MHz, CDCl₃) δ1.92-2.02 (2H, m), 2.42-2.70 (10H, m), 2.78 (2H, t, J=7.4Hz), 3.67 (3H, s), 4.00 (1H, s), 7.10-7.18 (2H, m), 7.27-7.41 (5H, m),7.48 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz), 8.47 (2H, s), 9.05 (1H,br s).

b) 1-(3- 5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl!propyl)-4-2-hydroxy-1-phenylethyl!piperazine

In the same way as that described in Example 5, Step 3, using methyl2-phenyl-2-1-(3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl)piperazin-4-yl!ethylacetate (620 mg, 1.35 mmol), LiAlH₄ (1.62 mL of a 1.0M solution inether, 1.62 mmol), THF (20 mL) and Na₂ SO₄ solution (sat., 5 mL). Thealcohol (485 mg, 84%) was isolated as a colourless foam. ¹ H NMR (360MHz, CDCl₃) δ1.81-1.90 (2H, m), 2.32-2.70 (10H, m), 2.74 (2H, t, J=7.6Hz), 3.64-3.70 (2H, m), 3.96 (1H, t, J=11 Hz), 7.11-7.19 (4H, m),7.28-7.35 (3H, m), 7.45 (1H, d, J=8.6 Hz), 7.52 (1H, d, J=2.0 Hz), 8.35(1H, br s), 8.44 (2H, s). MS (431, M+1).

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(imidazol-1-yl)-1-phenylethyl!piperazine. 2.5 Hydrogen Oxalate

In the same way as that described in Example 6, using 1-(3-5-(1,2,4-triazol-4-yl)-1H-indol-3-yl!propyl)-4-2-hydroxy-1-phenylethyl!piperazine (100 mg, 0.23 mmol), triethylamine(65 μL, 0.47 mmol), methanesulphonyl chloride (36 μL, 0.47 mmol) and THF(5 mL). The crude mesylate was then reacted with imidazole (317 mg, 4.7mmol) in the same way as that described in Example 6. The title compound(13 mg, 12%) was isolated as a pale yellow gum. The hydrogen oxalatesalt was prepared, mp. 130° C. (dec.). C₂₈ H₃₂ N₈. 2.5(C₂ H₂ O₄). 1.2(H₂O) requires: C, 54.50; H, 5.46; N, 15.41%. Found: C, 54.36; H, 5.48; N,15.59%. ¹ H NMR (250 MHz, d₆ -DMSO) δ1.95-2.12 (2H, m), 2.45-3.50 (14H,m), 5.65-5.70 (1H, m), 7.12 (1H, s), 7.33-7.51 (9H, m), 7.79 (1H, d,J=1.9 Hz), 8.27 (1H, s), 9.02 (2H, s), 11.19 (1H, br s). MS (ES⁺) (481,M+1).

EXAMPLE 11 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-phenyl-2-(pyrrolidin-1-yl)ethyl!piperazine. 2.4 Hydrogen Oxalate

In the same way as that described in Example 6, using 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-hydroxy-1-phenylethyl!piperazine (167 mg, 0.39 mmol), triethylamine(108 μL, 0.78 mmol), methanesulphonyl chloride (60 μL, 0.78 mmol) andTHF (8 mL). The crude mesylate was then reacted with pyrrolidine (0.65mL, 7.8 mmol) in the same way as that described in Example 6. The titleamine (39 mg, 21%) was isolated as pale yellow foam. The hydrogenoxalate salt was prepared. mp. 135° C. (dec.). C₂₉ H₃₇ N₇. 2.4(C₂ H₂O₄). H₂ O requires: C, 56.56; H, 6.15; N, 13.66%. Found: C, 56.65; H,6.35; N, 13.37%. ¹ H NMR (360 MHz, d₆ -DMSO) δ1.66-1.86 (4H, m),1.97-2.07 (2H, m), 2.43-3.33 (18H, m), 4.43-4.51 (1H, m), 7.29-7.34 (2H,m), 7.42-7.52 (6H, m), 7.79 (1H, s), 9.01 (2H, s), 11.17 (1H, br s). MS(ES⁺) (484, M+1).

EXAMPLE 12 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(oxazolidin-2-on-3-yl)-1-phenylethyl!piperazine. 1.25 Hydrogen Oxalate

Step 1

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-amino-1-phenylethyl!piperazine

In the same way as that described in Example 7, Step 1 using 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-hydroxy-1-phenylethyl!piperazine (330 mg, 0.77 mmol), triethylamine(214 μL, 1.53 mmol), methanesulphonyl chloride (118 μL, 1.53 mmol) andTHF (15 mL). The crude mesylate was then reacted with ammonia (7.7 mL ofa 2.0M solution in MeOH, 15.3 mmol) in the same way as that described inExample 7, Step 1. The amine (185 mg, 56%) was isolated as a pale yellowfoam. ¹ H NMR (250 MHz, CDCl₃) δ1.88-2.00 (2H, m), 2.38-2.76 (12H, m),2.79 (2H, t, J=7.5 Hz), 4.11 (1H, dd, J=10.4 and 3.6 Hz), 7.13-7.18 (2H,m), 7.22-7.39 (5H, m), 7.47 (1H, d, J=8.6 Hz), 7.59 (1H, s), 8.34 (1H,br s), 8.46 (2H, s). MS (430, M+1).

Step 2

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(2-(2-chloroethylcarbamoyl)-1-phenylethyl!piperazine

In the same way as that described in Example 7, Step 2, using 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-amino-1-phenylethyl!piperazine (138 mg, 0.32 mmol), 2-chloroethylchloroformate (35 μL, 0.34 mmol), NaOH solution (142 μL of a 10% (w/v)solution, 0.35 mmol), dioxane (3 mL) and water (1.5 mL). The carbamate(106 mg, 62%) was isolated as a colourless foam. ¹ H NMR (360 MHz,CDCl₃) δ1.88-1.99 (2H, m), 2.37-2.68 (12H, m), 2.77-2.83 (2H, m),3.50-3.77 (2H, m), 4.20-4.33 (2H, m), 4.61-4.71 (1H, m), 5.77-5.85 (1H,m), 7.13-7.16 (2H, m), 7.21-7.35 (5H, m), 7.46 (1H, d, J=8.5 Hz), 7.56(1H, d, J=2.0 Hz), 8.37 (1H, br s), 8.46 (2H, s). MS(ES⁺) (536/538,M+1).

Step 3

1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(oxazolidin-2-on-3-yl)-1-phenylethyl!piperazine. 1.25 Hydrogen Oxalate

In the same way as that described in Example 7, Step 3, using 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(2-chloroethylcarbamoyl)-1-phenylethyl!piperazine (106 mg, 0.2 mmol),sodium hydride (10 mg of a 60% dispersion in mineral oil, 0.25 mmol) andDMF (4 mL). The crude residue was chromatographed on silica gel, elutingwith CH₂ Cl₂ :MeOH:NH₃ (95:5:0.5). The title compound (87 mg, 87%) wasisolated as a colourless foam. The hydrogen oxalate salt was prepared.mp. 136° C. (dec.). C₂₈ H₃₃ N₇ O₂. 1.25(C₂ H₂ O₄). 0.25(H₂ O) requires:C, 59.41; H, 5.88; N, 15.90%. Found: C, 59.32; H, 5.96; N, 15.78%. ¹ HNMR (360 MHz, d₆ -DMSO) δ1.95-2.07 (2H, m), 2.49-3.14 (14H, m),3.26-3.34 (1H, m), 3.56-3.65 (1H, m), 4.20-4.33 (2H, m), 4.98-5.05 (1H,m), 7.30-7.41 (7H, m), 7.49 (1H, d, J=8.5 Hz), 7.80 (1H, d, J=2.0 Hz),9.01 (2H, s), 11.16 (1H, br s). MS (ES⁺) (500, M+1).

EXAMPLE 13 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(oxazol-2-on-3-yl)-1-phenylethyl!piperazine. 1.5 Hydrogen Oxalate

To a solution of 1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-hydroxy-1-phenylethyl!piperazine (100 mg, 0.23 mmol) in THF (5 mL) at0° C., was added triethylamine (49 μL, 0.35 mmol) followed bymethanesulphonyl chloride (27 μL, 0.35 mmol). The cooling bath wasremoved and the mixture stirred at room temperature for 35 min. Thesolid was removed by filtration and the filtrate partially evaporated(approx. 3 mL remaining) and diluted with DMF (5 mL). This filtrate wasthen added to a solution of oxazol-2-one sodium salt in DMF (2 mL). (Thesodium salt was prepared by adding sodium hydride (18.6 mg of a 60%dispersion in mineral oil, 0.47 mmol) to a solution of oxazol-2-one (40mg, 0.47 mmol) in DMF (2 mL) and stirring for 1 h at room temperature).The mixture was stirred at room temperature for 90 min then the solventwas removed in vacuo and the residue partitioned between CH₂ Cl₂ (2×25mL) and water (20 mL). The combined organic layers were dried (Na₂ SO₄)and evaporated. The residue was chromatographed on silica gel, elutingwith CH₂ Cl₂ :MeOH:NH₃ (90:10:0→90:10:1). The title compound (30 mg,26%) was isolated as a cream foam. The hydrogen oxalate salt wasprepared, mp. 125° C. (dec.). C₂₈ H₃₁ N₇ O₂. 1.5(C₂ H₂ O₄). 0.5(H₂ O)requires: C, 58.03; H, 5.50; N, 15.28%. Found: C, 58.23; H, 5.73; N,15.38%. ¹ H NMR (360 MHz, d₆ -DMSO) δ1.93-2.07 (2H, m), 2.47-3.30 (14H,m), 5.15-5.21 (1H, m), 7.21 (1H, d, J=2.0 Hz), 7.27-7.40 (8H, m), 7.49(1H, d, J=8.6 Hz), 7.79 (1H, d, J=1.9 Hz), 9.01 (2H, s), 11.16 (1H, brs). MS (ES⁺) (498, M+1).

EXAMPLE 14 1- 3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-(imidazol-1-yl)-1-phenylpropyl!piperazine. 2.5 Hydrogen Oxalate

In the same way as that described in Example 6, using 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-hydroxy-1-phenylpropyl!piperazine (200 mg, 0.45 mmol), triethylamine(125 μL, 0.9 mmol), methanesulphonyl chloride (70 μL, 0.9 mmol) and THF(10 mL). The crude mesylate was then reacted with imidazole (613 mg, 9.0mmol) in the same way as that described in Example 6, to give the titlecompound (57 mg, 26%) as a pale yellow foam. The hydrogen oxalate saltwas prepared. mp. 90° C. (dec.). C₂₉ H₃₄ N₈. 2.5(C₂ H₂ O₄). 2.5(H₂ O)requires: C, 53.40; H, 5.80; N, 14.65%. Found: C, 53.34; H, 5.86; N,14.50%. ¹ H NMR (360 MHz, d₆ -DMSO) δ1.98-2.09 (2H, m), 2.26-2.43 (4H,m), 2.57-2.81 (6H, m), 2.98-3.21 (6H, m), 5.46-5.55 (1H, m), 7.11 (1H,s), 7.27-7.42 (7H, m), 7.46 (1H, s), 7.51 (1H, d, J=8.6Hz), 7.81 (1H,s), 8.20 (1H, s), 9.02 (2H, s), 11.18 (1H, br s). MS (ES⁺) (495, M+1).

We claim:
 1. A compound of formula I, or a salt thereof: ##STR22##wherein R¹ represents hydrogen, halogen, trifluoromethyl, C₁₋₆ alkoxy ora group of formula (a): ##STR23## R² and R³ independently representhydrogen, halogen, trifluoromethyl or C₁₋₆ alkoxy;E represents astraight or branched alkylene chain containing from 1 to 4 carbon atoms;and Z represents hydroxy, C₁₋₆ alkoxy, aryl(C₁₋₆)alkoxy, an imidazolylor pyrrolidinyl group, or a group of formula (Za) or (Zb): ##STR24## inwhich the broken line represents an optional chemical bond; and R⁴represents C₁₋₆ alkyl.
 2. A compound as claimed in claim 1 representedby formula II, and salts thereof: ##STR25## wherein R¹, R² and R³ are asdefined in claim 1; e is 1 or 2; andZ¹ represents hydroxy, methoxy,benzyloxy, imidazol-1-yl, pyrrolidin-1-yl, oxazol-2-on-3-yl,oxazolidin-2-on-3-yl or 5-methyl-1,2,4-oxadiazol-3-yl.
 3. A compound asclaimed in claim 2 wherein R¹ represents hydrogen, fluoro ortrifluoromethyl.
 4. A compound as claimed in claim 2 wherein R² ishydrogen and R³ is other than hydrogen.
 5. A compound as claimed inclaim 2 wherein R² and R³ are both hydrogen.
 6. A compound as claimed inclaim 3 wherein R² is hydrogen and R³ is other than hydrogen.
 7. Acompound as claimed in claim 3 wherein R² and R³ are both hydrogen.
 8. Acompound selected from:1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(oxazol-2-on-3-yl)-1-phenylethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(oxazolidin-2-on-3-yl)-1-phenylethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-(oxazolidin-2-on-3-yl)ethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-(3-hydroxy-1-phenylpropyl)piperazine;1- 3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-(imidazol-1-yl)-1-phenylethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-hydroxyethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-methoxyethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1-phenylpropyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-2-benzyloxy-1-(4-fluorophenyl)ethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-3-methoxypropyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-2-(imidazol-1-yl)ethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-phenyl-2-(pyrrolidin-1-yl)ethyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-1-(4-fluorophenyl)-3-hydroxypropyl!piperazine; 1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl!-4-3-(imidazol-1-yl)-1-phenylpropyl!piperazine;and salts thereof.
 9. Apharmaceutical composition comprising a compound of formula I as definedin claim 1 or a pharmaceutically acceptable salt thereof thereof inassociation with a pharmaceutically acceptable carrier.
 10. A processfor the preparation of a compound as claimed in any one of claims 1 to6, which comprises:(A) reacting the compound of formula III with acompound of formula IV: ##STR26## wherein R¹, R², R³, E and Z are asdefined in claim 1, and L¹ represents a suitable leaving group; or (B)reacting the compound of formula III as defined above with a compound offormula V: ##STR27## wherein R¹, R², R³, E and Z are as defined in claim1; in the presence of a reducing agent; or (C) reacting the compound offormula VI: ##STR28## with a compound of formula XI, or acarbonyl-protected form thereof: ##STR29## wherein R¹, R², R³, E and Zare as defined in claim 1; or (D) reacting a compound of formula XIII:##STR30## wherein R¹, R², R³, E and Z are as defined in claim 1; with acompound of formula XIV: ##STR31## wherein L³ represents a suitableleaving group; or (E) reducing a compound of formula XVII: ##STR32##wherein R¹, R², R³, E and Z are as defined in claim 1; or (F) reducing acompound of formula XIX: ##STR33## wherein E¹ represents a chemical bondor a straight or branched alkylene chain containing from 1 to 3 carbonatoms, R^(x) represents C₁₋₆ alkyl, and R¹, R² and R³ are as defined inclaim 1; or (G) reacting a compound of formula XX with a compound offormula XXI: ##STR34## wherein Z² represents imidazol-1-yl,pyrrolidin-1-yl, oxazol-2-on-3-yl or oxazolidin-2-on-3-yl, L⁵ representsa suitable leaving group, and R¹, R², R³ and E are as defined inclaim
 1. 11. A method for the treatment and/or prevention of migraine,cluster headache, chronic paroxysmal hemicrania, headache associatedwith vascular disorders, tension headache or paediatric migraine, whichmethod comprises administering to a patient in need of such treatment aneffective amount of a compound of formula I as defined in claim 1 or apharmaceutically acceptable salt thereof.